Regulation of electrogenic anion secretion in normal and cystic fibrosis gallbladder mucosa

Fluid and ion transport across biliary epithelium contributes to bile flow. Alterations of this function may explain hepatobiliary complications in cy stic fibrosis (CF). We investigated electrogenic anion transport across int act non-CF and CF human gallbladder mucosa in Ussing-type chambers. In non- CF tissues, baseline transmural potential difference (PD), short-circuit cu rrent (Isc), and resistance (R) were -2.2 +/- 0.3 mV (lumen negative), 40.7 +/- 7.8 mu A/cm(2), and 66.5 +/- 9.6 Omega . cm(2), respectively (n = 14), The addition of forskolin (10(-5) mol/L) to the apical and basolateral bat hs and that of adenosine 5'-triphosphate (ATP) (10(-4) mol/L) to the apical bath induced significant increases in Isc by 8.0 +/- 1.4 and 10.3 +/- 1.8 mu A/cm(2), respectively. Depletion of bathing solutions in Cl- and HCO3- s ignificantly reduced baseline Isc and the forskolin- and ATP-induced increa ses in Isc, Anion secretion was stimulated by extracellular ATP via P2Y(2) purinoceptors, as indicated by the effects of different nucleotides on Isc and on Cl-36 efflux in cultured gallbladder epithelial cells. This effect w as mediated by cytosolic calcium increase and Ca2+/calmodulin-dependent pro tein kinase II, as ascertained by using inhibitors. In CF preparations, bas al PD and Ise were lower than in non-CF, and the response to forskolin was abolished, whereas the response to ATP was enhanced (P <.05 for all). We co nclude that electrogenic anion secretion occurs in human gallbladder mucosa under basal state and is stimulated by an adenosine 3',5'-cyclic monophosp hate (cAMP)dependent pathway mediated by cystic fibrosis transmembrane cond uctance regulator (CFTR), and by exogenous ATP via a CFTR-independent pathw ay that is up-regulated in CF and involves P2Y(2) purinoceptors and a calci um-dependent pathway.